Overview

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion called Rictor, mammalian stress-activated protein map kinase-interacting protein 1 (mSin1 or MAPKAP1).  Mammalian lethal with SEC13 protein 8 (mLST8) is a common protein of both complexes.

The binding of insulin to the insulin receptor, an RTK, initiates the mTOR pathway. The activated receptors auto-phosphorylate tyrosine 960 on its cytoplasmic domain. The phosphorylated tyrosine forms a docking site for the insulin receptor substrate (IRS) that binds the receptor via their phospho-tyrosine binding (PTB) domain. In addition, IRS contains a PH domain that helps them bind phosphoinositides on the plasma membrane.  At least four types of IRS (IRS-1 to 4) assist in insulin receptor signaling. Once bound to the receptor, multiple tyrosines on the IRS are phosphorylated, which recruits the SH2 domain-containing phosphatidylinositol-3-kinase or PI-3K to the cytosolic surface of the plasma membrane. The PI-3K binds to the phosphatidylinositol (4,5)-bisphosphate  (PIP2) and produces phosphatidylinositol (3,4,5)-trisphosphate or PIP3. Adjacent PIP3 functions as docking sites for protein kinase B (PKB) or AKT and 3-phosphoinositide-dependent kinase 1 or PDK1. As mTORC2 phosphorylates AKT at serine 473, it undergoes a conformational change and exposes a threonine 308 residue, which subsequently leads to phosphorylation of the AKT by PDK1.

Activated AKT dissociates from the membrane to phosphorylate a series of downstream targets to promote cell growth, proliferation, and other responses. For example, the forkhead transcription factor, FOXO3a, is a transcription factor that activates the transcription of pro-apoptotic proteins.  Phosphorylation of FOXO3a by AKT induces its binding to 14-3-3 protein and its subsequent sequestration in the cytosol, thereby promoting cell survival. Activated Akt also inhibits tuberous sclerosis protein 2 or Tsc 2 and promotes Rheb activation. Activated Rheb (Rheb-GTP) further stimulates mTORC1 and induces cell growth. 

Procedure

The PI3K/mTOR/AKT signaling pathway transmits signals to regulate the cell cycle.

It starts when insulin binding phosphorylates specific tyrosines on its receptor, an RTK, which acts as a binding site for phosphatidylinositol-3-kinase or PI-3K.

Activated PI-3K binds phosphatidylinositol (4,5)-bisphosphate or PIP2 and phosphorylates it to produce phosphatidylinositol (3,4,5)-trisphosphate or PIP3.

Adjacent PIP3s act as anchoring sites for two PH domain-containing proteins: protein kinase B or PKB, also known as AKT , and 3-phosphoinositide-dependent kinase 1 or PDK1.

A kinase called the mammalian target of rapamycin complex 2  or mTORC 2 phosphorylates a serine residue on AKT.

This induces conformational changes in AKT, allowing phosphorylation by the nearby PDK1.

Activated AKT dissociates from the membrane to phosphorylate downstream targets, promoting cell growth and proliferation.